Implantable drug depot for weight control

ABSTRACT

The present invention is directed to an implantable drug depot for weight control. The drug depot includes at least one biodegradeable polymer and at least one biologically active agent. Through the administration of an effective amount of the biologically active agent at or near a target site, one can control weight gain and/or reduce, prevent or treat obesity. When appropriate formulations are provided within biodegradable polymers, weight control or treatment can be conducted for at least five days and up to one hundred and thirty-five days.

BACKGROUND OF THE INVENTION

Sixty-six percent of adults in the United States are overweight orobese. Obesity is a medical condition in which excess body fat hasaccumulated to the extent that it may have an adverse effect on aperson's health leading to reduced life expectancy. Obesity is anepidemic in the United States and in other developed countries as nearlyone-third of the population is obese. Further, obesity is on the rise asfood is abundant and physical activity is optional.

Obesity has many serious long-term consequences and it is the secondleading cause of preventable deaths in the United States. It isassociated with many diseases, particularly heart disease, type 2diabetes, breathing difficulties during sleep, certain types of cancerand osteoarthritis. Obesity is most commonly caused by a combination ofexcessive dietary calories, lack of physical activity and geneticsusceptibility.

Billions of dollars are spent each year on weight control and obesitytreatments. In addition, approximately $45 billion is spent each year ontreating the diseases associated with obesity. Furthermore, businessessuffer an estimated $20 billion loss in productivity each year fromabsence due to illness caused by obesity.

The primary treatment for obesity is dieting and physical exercise. Ifthis fails, anti-obesity drugs may be taken to reduce appetite orinhibit fat absorption. In severe cases, surgery is performed or anintragastric balloon is placed to reduce stomach volume and or bowellength, leading to earlier satiation and reduced ability to absorbnutrients from food.

As far as anti-obesity medications, only two are currently approved bythe U.S. Food and Drug Administration (“FDA”) for long term use.Orlistat (Xenical) is currently approved by the FDA and it reducesintestinal fat absorption by inhibiting pancreatic lipase. Sibutramine(Meridia) is also approved by the FDA and it acts in the brain toinhibit deactivation of the neurotransmitters norepinephrine, serotoninand dopamine thereby decreasing appetite. A third medication, Rimonabant(Acomplia), is approved in Europe and it works by blocking theendocannabinoid system. Weight loss with these drugs has been shown tobe modest with the following average weight losses: Orlistat—6.4 lbs;Sibutramine—9.3 lbs; and Rimonabant—10.4 lbs.

Accordingly, there is a need to develop more effective pharmaceuticalssince maintaining a healthy body weight and/or avoiding obesity can helpcontrol cholesterol, blood pressure and blood sugar which can helpprevent weight-related diseases, such as heart disease, diabetes,arthritis and some cancers.

One pharmaceutical with minimal side effects that is known to themedical profession is clonidine, which is widely recognized as anantihypertensive agent that acts as an agonist on the alpha-2-adrenergicreceptor and a neural receptor agonist. In general, clonidine, alsoreferred to as 2,6-dichloro-N-2-imidazolidinyldenebenzenamine(C₉H₉Cl₂N₃), may be represented by the following chemical structure:

Another compound is fluocinolone which is known to the medicalprofession for reducing inflammation and/or immunological rejection oftransplanted tissue. Fluocinolone in its acetonide form (C24H30F2O6) hasbeen administered topically as a cream in connection with handtransplants. It may also be referred to as4b,12-Difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-2-one or 6α-,9α-Difluoro-16 α-hydroxyprednisolone16,17-acetonide.

However, to date, neither clonidine nor fluocinolone have been widelyappreciated as a treatment for weight control and/or reduction orprevention of obesity. This invention is directed to effectiveformulations including one or both of these compounds for theseapplications.

SUMMARY OF THE INVENTION

Compositions and methods are provided comprising a biologically activeagent or its pharmaceutically acceptable salts that are administered forweight control and/or in order to treat, prevent or reduce obesity.

In one exemplary embodiment, an implantable drug depot for weightcontrol in a patient in need of such treatment is provided. The drugdepot comprises at least one biodegradeable polymer and at least onebiologically active agent in an amount from about 0.1 wt. % to about 30wt. % of the drug depot. The drug depot is capable of releasing thebiologically active agent over a period of 5 to 135 days. Thebiologically active agent comprises clonidine or a pharmaceuticallyacceptable salt thereof and/or fluocinolone or a pharmaceuticallyacceptable salt thereof. The biologically active agent can be releasedat an amount between 0.005 and 1.0 mg per day for the period of 5 to 135days.

In another exemplary embodiment, an implantable drug depot for weightcontrol in a patient in need of such treatment is provided, wherein thedrug depot comprises at least one biodegradeable polymer and at leastone biologically active agent or a pharmaceutically acceptable saltthereof in an amount from about 0.1 wt. % to about 30 wt. % of the drugdepot, and the drug depot releases: (i) a bolus dose of the biologicallyactive agent; and (ii) an effective amount of the biologically activeagent over a period of at least fifty days. The biologically activeagent comprises clonidine or a pharmaceutically acceptable salt thereofand/or fluocinolone or a pharmaceutically acceptable salt thereof.

In another exemplary embodiment, a method for weight control and/orreducing, preventing or treating obesity is provided. The methodcomprises implanting a drug depot in an organism for weight control,wherein the drug depot comprises a biologically active agent in anamount from about 0.1 wt. % to about 30 wt. % of the drug depot, and atleast one biodegradable polymer. The biologically active agent iscapable of being released in an amount between 0.005 and 1.0 mg per dayfor a period of 5 to 135 days. The biologically active agent comprisesclonidine or a pharmaceutically acceptable salt thereof and/orfluocinolone or a pharmaceutically acceptable salt thereof.

In still another exemplary embodiment, another method for weight controland/or reducing, preventing or treating obesity is provided. The methodcomprises implanting a drug depot in an organism for weight controland/or reducing, preventing or treating obesity. The drug depotcomprises a biologically active agent in an amount from about 0.1 wt. %to about 30 wt. % of the drug depot, and at least one biodegradablepolymer. The drug depot is capable of releasing about 5% to about 100%of the biologically active agent relative to a total amount of thebiologically active agent loaded in the drug depot over a period of 3 to200 days after the drug depot is implanted in the organism. Thebiologically active agent comprises clonidine or a pharmaceuticallyacceptable salt thereof and/or fluocinolone or a pharmaceuticallyacceptable salt thereof.

In still yet another exemplary embodiment, an implantable drug depotuseful for weight control and/or reducing, preventing or treatingobesity in a patient in need of such treatment is provided, wherein thedrug depot comprises at least one biodegradeable polymer and atherapeutically effective amount of clonidine and/or fluocinolone, thedrug depot is administered at a site for weight control and/or reducing,preventing or treating obesity, and the drug depot is capable ofreleasing clonidine and/or fluocinolone at an amount between 0.005 and1.0 mg per day for a period of 5 to 135 days at the site.

In another exemplary embodiment, there is a sustain release compositioncomprising an effective amount of a biologically active agent in animplantable drug depot, wherein the biologically active agent is presentin an amount to control weight and/or reduce, prevent or treat obesityfor a period of 5 to 135 days and wherein the implantable drug depotfacilitates sustain release of the biologically active agent over theperiod. The biologically active agent comprises clonidine or apharmaceutically acceptable salt thereof and/or fluocinolone or apharmaceutically acceptable salt thereof.

In another exemplary embodiment, a method of making an implantable drugdepot is provided. The method comprises combining a biocompatiblepolymer and a therapeutically effective amount of a biologically activeagent and forming the implantable drug depot from the combination. Thebiologically active agent comprises clonidine or a pharmaceuticallyacceptable salt thereof and/or fluocinolone or a pharmaceuticallyacceptable salt thereof.

When clonidine is the biological active agent, it may be in the form ofa salt. One example of a salt is a hydrochloric salt. Clonidine mayalternatively be in the form of a base. In addition, clonidine may be inthe form of a mixture of clonidine base and a hydrochloride salt.Further, clonidine or a pharmaceutically acceptable salt thereof may beencapsulated in a plurality of depots comprising microparticles,microspheres, microcapsules, and/or microfibers which could be suspendedin a gel. The drug depot may be a pellet. Clonidine or apharmaceutically acceptable salt thereof may be present in variousembodiments in an amount from about 0.1 wt. % to about 30 wt. % of thedrug depot. In some embodiments, clonidine may comprise from about 5 wt.% to about 15 wt. % of the drug depot.

When fluocinolone is the biological active agent, it may be in the formof a salt. One example of a salt is fluocinolone acetonide.

The polymer in various embodiments of this invention comprises one ormore of poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-c-caprolactone, andD,L-lactide-co-glycolide-co-ε-caprolactone. Further, the polymer iscapable of degrading or degrades in 200 days or less after the drugdepot is administered for weight control and/or to reduce, prevent ortreat obesity. Also, the polymer may comprise at least about 70% of thetotal wt. % of the drug depot. In various embodiments, the polymer maycomprise poly(lactic-co-glycolic acid) and the poly(lactic-co-glycolicacid) comprises a mixture of polyglycolide and polylactide. The mixturecan comprise more polylactide than polyglycolide.

The drug depot in various embodiments is capable of releasing between0.005 and 3 milligrams (mg) per day of the biologically active agent forweight control and/or to reduce, prevent or treat obesity. In someembodiments, the drug depot is capable of releasing between 0.01 and 0.1mg per day of the biologically active agent for weight control and/or toreduce, prevent or treat obesity.

The drug depot in various embodiments may comprise a radiographic markeradapted to assist in radiographic imaging. The radiographic marker maycomprise barium, bismuth, tungsten, tantalum, iodine, calcium phosphateand/or metal beads.

The drug depot in various embodiments may comprise at least oneadditional anti-inflammatory or analgesic agent, at least one anabolicor an anti-catabolic growth factor or a combination thereof.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 is a table of fourteen formulations of the present invention thatcomprise fluocinolone as the biologically active agent.

FIG. 2 is a graphic representation of the fluocinolone cumulative invitro release profile as measured by the cumulative API releasepercentage for several of the formulations from the table in FIG. 1.

FIG. 3 is a graphic representation of the calculated daily microgramsreleased of fluocinolone for certain formulations from the table in FIG.1.

FIG. 4 is a table of a number of additional formulations of the presentinvention that comprise fluocinolone as the biologically active agent.

FIG. 5 is a graphic representation of an in vitro release of clonidineas measured by percentage release from three pellet formulations of thepresent invention that comprise clonidine as the biologically activeagent.

FIG. 6 is a graphic representation of the calculated daily release ofclonidine as measured by micrograms released in vitro from three pelletformulations of the present invention that comprise clonidine as thebiologically active agent.

FIG. 7 is a graphic representation of clonidine HCl release for variousformulations as measured by the cumulative clonidine releasedpercentage.

FIG. 8 is a graphic representation of the cumulative in vitro releaseprofile for certain formulations of the present invention that compriseclonidine as the biologically active agent.

FIG. 9 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations.

FIG. 10 is a graphic representation of certain calculated daily releasemeasurements of clonidine from 2/3/4 pellets doses.

FIG. 11 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses.

FIG. 12 is a graphic representation of the cumulative in vitro releaseprofile of clonidine from certain coaxial formulations.

FIG. 13 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations.

FIG. 14 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations.

FIG. 15 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain 3/4/5 pellet dose formulations.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 27 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 31 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 32 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 35 is a set of four graphs that depict in vitro elution data for anumber of fluocinolone formulations.

FIG. 36 is a set of three graphs that depict in vitro elution data for anumber of formulations of the present invention that comprisefluocinolone as the biologically active agent.

FIG. 37 shows in vivo plasma serum levels and in vitro elution profilesfor exemplary formulations of the present invention that comprisefluocinolone as the biologically active agent.

FIG. 38 shows in vitro elution profiles and in vivo plasma serum levelsfor exemplary formulations of the present invention that comprisefluocinolone as the biologically active agent.

FIG. 39 shows the results of a study in which the body weight change forfour groups of rats was evaluated wherein three groups of rats receivedfluocinolone via subcutaneous injection daily and one group of ratsreceived saline injections daily.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

A “drug depot” is the composition in which the biologically active agentis administered to the body. Thus, a drug depot may comprise a physicalstructure to facilitate implantation and retention in a desired site.The drug depot may also comprise the biologically active agent or drugitself. The term “drug” as used herein is generally meant to refer toany substance that alters the physiology of a patient. The term “drug”may be used interchangeably herein with the terms “biologically activeagent,” “therapeutic agent,” and “active pharmaceutical ingredient” or“API.” It will be understood that unless otherwise specified a “drug”formulation may include more than one therapeutic agent, whereinexemplary combinations of therapeutic agents include a combination oftwo or more drugs. The drug provides a concentration gradient of thetherapeutic agent for delivery to the site. In various embodiments, thedrug depot provides an optimal drug concentration gradient of thetherapeutic agent at a distance of up to about 0.01 cm to about 5 cmfrom the administration site and comprises clonidine and/orfluocinolone. A drug depot may also include a pump or pellet.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition, reduction or alleviation ofobesity and/or maintaining body weight, etc. The dosage administered toa patient can be single or multiple doses depending upon a variety offactors, including the drug's administered pharmacokinetic properties,the route of administration, patient conditions and characteristics(sex, age, body weight, health, size, etc.), extent of obesity or excessbody weight, concurrent treatments, frequency of treatment and theeffect desired. In some embodiments, the formulation is designed forimmediate release. In other embodiments, the formulation is designed forsustained release. In other embodiments, the formulation comprises oneor more immediate release surfaces and one or more sustained releasesurfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible,” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable,” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

In some embodiments, the drug depot has pores that allow release of thedrug from the depot. The drug depot will allow fluid in the depot todisplace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot should not function as a tissue scaffold andallow tissue growth. Rather, the drug depot will solely be utilized fordrug delivery. In some embodiments, the pores in the drug depot will beless than 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example, a bolus or immediate release formulation of clonidineand/or fluocinolone may be placed at or near the target site and asustain release formulation may also be placed at or near the same site.Thus, even after the bolus becomes completely accessible, the sustainrelease formulation would continue to provide the active ingredient(s)for the intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-four toseventy-two hours after implantation. “Initial burst” or “burst effect”or “bolus dose” refers to the release of therapeutic agent from thedepot during the first twenty-four hours to seventy-two hours after thedepot comes in contact with an aqueous fluid (e.g., synovial fluid,cerebral spinal fluid, etc.). The “burst effect” is believed to be dueto the increased release of therapeutic agent from the depot. Inalternative embodiments, the depot (e.g., gel) is designed to avoid orreduce this initial burst effect (e.g., by applying an outer polymercoating to the depot).

“Treating” or “treatment” for weight control and/or obesity refers toexecuting a protocol that may include administering one or more drugs toa patient (human, other normal or otherwise or other mammal), in aneffort to control weight and/or reduce or alleviate obesity or excessbody weight. Alleviation can occur prior to signs or symptoms of obesityas well as after its appearance. Thus, treating or treatment includespreventing or prevention of obesity or excess body weight conditions. Inaddition, treating or treatment does not require complete alleviation ofobesity or excess body weight conditions, does not require a cure, andspecifically includes protocols that have only a marginal effect on thepatient. Reducing obesity or excess body weight includes a decrease inobesity conditions or excess body weight and does not require completealleviation of obesity conditions or excess body weight, and does notrequire a cure. In various embodiments, reducing obesity or excess bodyweight includes even a marginal decrease in obesity conditions or excessbody weight. By way of example, the administration of the effectivedosage of clonidine and/or fluocinolone may be used to prevent, treat orreduce obesity or excess body weight.

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., drug depot) retaining potential for successful placementwithin a mammal. The expression “implantable device” and expressions ofthe like import as utilized herein refers to an object implantablethrough surgery, injection, or other suitable means whose primaryfunction is achieved either through its physical presence or mechanicalproperties.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 0.1cm, or preferably within about 10 cm, for example) thereto. For example,the drug dose delivered locally from the drug depot may be, for example,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% lessthan the oral dosage or injectable dose. In turn, systemic side effects,such as for example, liver transaminase elevations, hepatitis, liverfailure, myopathy, constipation, etc. may be reduced or eliminated.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, 10% per day for ten days, etc. As persons of ordinary skillknow, a release rate profile may, but need not, be linear. By way of anon-limiting example, the drug depot may be a pellet that releases theclonidine and/or fluocinolone over a period of time (see FIGS. 2, 3 and5-38).

The term “solid” is intended to mean a rigid material, while,“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

“Targeted delivery system” provides delivery of one or more drugsdepots, gels or depots dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded for weight control treatment and/or prevention, reduction ortreatment of obesity.

The term “obesity” is defined as a medical condition in which excessbody fat has accumulated to the extent that it may have an adverseeffect on a person's health leading to reduced life expectancy.

“Biologically active agent” as used herein is intended to mean acomposition comprising clonidine or a pharmaceutically acceptable saltthereof and/or fluocinolone or a pharmaceutically acceptable saltthereof. The term “biologically active agent” may be usedinterchangeably herein with the terms “drug,” “therapeutic agent,”“active pharmaceutical ingredient,” or “API.”

“Excess body weight” refers to a mammal or patient having a body massindex (BMI) (which takes into account weight and height of a person)that is greater than a healthy BMI range for a mammal or patient havinga certain weight and height. The Centers for Disease Control andPrevention provides ranges for BMI for adults and children.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “POE” refers to poly(orthoester).

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

Fluocinolone

When referring to fluocinolone, unless otherwise specified or apparentfrom context, it is understood that the inventors are also referring topharmaceutically acceptable salts, pharmacologically-active derivativesof fluocinolone or an active metabolite of fluocinolone. As used herein,“pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds (e.g., esters or amines) wherein the parent compoundmay be modified by making acidic or basic salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,or nitric acids; or the salts prepared from organic acids such asacetic, fuoric, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionicacid. Pharmaceutically acceptable also includes the racemic mixtures((+)-R and (−)-S enantiomers) or each of the dextro and levo isomers ofthe fluocinolone individually. Fluocinolone may be in the free acid orbase form or be pegylated for long acting activity.

One common form of fluocinolone for administration to mammals isfluocinolone acetonide.

Clonidine

When referring to clonidine, unless otherwise specified or apparent fromcontext, it is understood that the inventors are also referring topharmaceutically acceptable salts. One well-known commercially availablesalt for clonidine is its hydrochloride salt. Some other examples ofpotentially pharmaceutically acceptable salts include those salt-formingacids and bases that do not substantially increase the toxicity of acompound, such as, salts of alkali metals such as magnesium, potassiumand ammonium, salts of mineral acids such as hydriodic, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, as well as saltsof organic acids such as tartaric, acetic, citric, malic, benzoic,glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.,p-toluenesulfonic acids, and the like.

Further, when referring to clonidine, the active ingredient may not onlybe in the salt form, but also in the base form (e.g., free base). Invarious embodiments, if it is in the base form, it may be combined withpolymers under conditions in which there is not severe polymerdegradation, as may be seen upon heat or solvent processing that mayoccur with PLGA or PLA. By way of a non limiting example, whenformulating clonidine with poly(orthoesters) it may be desirable to usethe clonidine base formulation. By contrast, when formulating clonidinewith PLGA, it may be desirable to use the HCl salt form. In someembodiments, clonidine may be incorporated into a polymer core with apolymer and then coated with the same or different polymer.

The biologically active agent may be administered with a musclerelaxant. Exemplary muscle relaxants include by way of example and notlimitation, alcuronium chloride, atracurium bescylate, baclofen,carbamate, carbolonium, carisoprodol, chlorphenesin, chlorzoxazone,cyclobenzaprine, dantrolene, decamethonium bromide, fazadinium,gallamine triethiodide, hexafluorenium, meladrazine, mephensin,metaxalone, methocarbamol, metocurine iodide, pancuronium, pridinolmesylate, styramate, suxamethonium, suxethonium, thiocolchicoside,tizanidine, tolperisone, tubocuarine, vecuronium or combinationsthereof.

The drug depot may comprise another therapeutic agent in addition to thebiologically active agent. Exemplary therapeutic agents may block thetranscription or translation of TNF-α or other proteins in theinflammation cascade. Suitable therapeutic agents include, but are notlimited to, integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, CTLA4-Igagonists/antagonists (BMS-188667), CD40 ligand antagonists, Humanizedanti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1 mAb (CriticalTherapeutics Inc.), anti-IL2R antibodies (daclizumab, basilicimab), ABX(anti IL-8 antibodies), recombinant human IL-10 or HuMax IL-15 (anti-IL15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression) andaurin-tricarboxylic acid (which inhibits TNF-α), may also be useful astherapeutic agents for reducing inflammation. It is further contemplatedthat where desirable a pegylated form of the above may be used. Examplesof still other therapeutic agents include NF kappa B inhibitors such asglucocorticoids, antioxidants such as dithiocarbamate, and othercompounds, such as, for example, sulfasalazine.

Examples of therapeutic agents suitable for use also include but are notlimited to an anti-inflammatory agent, an analgesic agent, or anosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine [2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin or tolmetin; as well as antioxidants, such asdithiocarbamate, steroids, such as cortisol, cortisone, hydrocortisone,fludrocortisone, prednisone, prednisolone, methylprednisolone,triamcinolone, betamethasone, dexamethasone, beclomethasone, fluticasoneor a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include butare not limited to a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Suitable analgesic agents include but are not limited to acetaminophen,bupivacaine, lidocaine, opioid analgesics such as buprenorphine,butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine,fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone,ketobemidone, levomethadyl, mepiridine, methadone, morphine, nalbuphine,opium, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol,codeine, dihydrocodeine, meptazinol, dezocine, eptazocine, flupirtine,amitriptyline, carbamazepine, gabapentin, pregabalin or a combinationthereof.

The biologically active agent may also be administered with non-activeingredients. These non-active ingredients may have multi-functionalpurposes including the carrying, stabilizing and controlling the releaseof the biologically active agent(s). The sustained release process, forexample, may be by a solution-diffusion mechanism or it may be governedby an erosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

Exemplary excipients that may be formulated with the biologically activeagent (clonidine and/or fluocinolone) in addition to the biodegradablepolymer include but are not limited to MgO (e.g., 1 wt. %), 5050 DLG 6E(Lakeshore Biomaterials, Birmingham, Ala.), 5050 DLG 1A (LakeshoreBiomaterials, Birmingham, Ala.), mPEG, TBO-Ac, mPEG, Span-65, Span-85,pluronic F127, TBO-Ac, sorbitol, cyclodextrin, maltodextrin, pluronicF68, CaCl, 5050 DLG-7A (Lakeshore Biomaterials, Birmingham, Ala.) andcombinations thereof. In some embodiments, the excipients comprise fromabout 0.001 wt. % to about 50 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 40wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 30 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 20wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 10 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 50wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 2 wt. % of the formulation.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to or greater than(for biodegradable components and non-biodegradable components) theplanned period of drug delivery.

In some embodiments, the depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thebiologically active agent. However, the pre-determined erosion of thedepot material can also be used to provide for slow release of theloaded biologically active agent(s). Non-biodegradable polymers includebut are not limited to PVC and polyurethane.

In some embodiments, the drug depot may not be fully biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics, methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO(pluronics) or combinations thereof. Typically, these types of drugdepots may need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioerodible, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release or sustained release of the biologically active agent.Examples of suitable sustained release biopolymers include but are notlimited to poly(alpha-hydroxy acids), poly(lactide-co-glycolide),polylactide, polyglycolide (PG), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, polyhydroxybutyrate,poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine),poly(lactide-co-urethane), poly(ester-co-amide), PEG conjugates of poly(alpha-hydroxy acids), poly(orthoester)s, polyaspirins,polyphosphazenes, polyanhydrides; polyketals, collagen, starch,pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates,albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate,d-alpha tocopheryl succinate, ε-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate) or combinations thereof. As persons of ordinaryskill are aware, mPEG may be used as a plasticizer for PLGA, but otherpolymers/excipients may be used to achieve the same effect. mPEG impartsmalleability to the resulting formulations. In some embodiments, thesebiopolymers may also be coated on the drug depot to provide the desiredrelease profile. In some embodiments, the coating thickness may be thin,for example, from about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 micronsto thicker coatings 60, 65, 70, 75, 80, 85, 90, 95, 100 microns to delayrelease of the drug from the depot. In some embodiments, the range ofthe coating on the drug depot ranges from about 5 microns to about 250microns or 5 microns to about 200 microns to delay release from the drugdepot.

As persons of ordinary skill in the art are aware, when an implantabledepot composition having a blend of polymers with different end groupsis used, the resulting formulation will have a lower burst index and aregulated duration of delivery. For example, one may use polymers withacid (e.g., carboxylic acid) and ester end groups (e.g., methyl or ethylester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer), there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower initial burst and aregulated duration of delivery.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfite, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be of different sizes, shapes and configurations. Thereare several factors that can be taken into consideration in determiningthe size, shape and configuration of the drug depot. For example, boththe size and shape may allow for ease in positioning the drug depot atthe target tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a pellet, aflat surface such as a disc, film or sheet (e.g., ribbon-like) or thelike. Flexibility may be a consideration so as to facilitate placementof the drug depot. In various embodiments, the drug depot can bedifferent sizes, for example, the drug depot may be a length of fromabout 0.5 mm to 5 mm and have a diameter of from about 0.01 to about 4mm. In various embodiments, as the diameter decreases, the surface areathat comes in contact with the bodily fluid of the depot increases andtherefore release of the drug from the depot increases. In variousembodiments, the drug depot may have a layer thickness of from about0.005 to 1.0 mm, such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, bismuth, iodine, tantalum, tungsten and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

There a number of common locations within a patient that may be sites atwhich the drug depot may be administered. For example, administrationmay be required in a patient's arms, shoulders, knees, hips, fingers,thumbs, neck and/or spine.

Gel

In various embodiments, the biologically active agent is administered ina gel. The gel may have a pre-dosed viscosity in the range of about 1 toabout 2000 centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps.After the gel is administered to the target site, the viscosity of thegel will increase and the gel will have a modulus of elasticity (Young'smodulus) in the range of about 1×−10² to about 6×10⁵ dynes/cm², 2×10⁴ toabout 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, a depot comprises an adherent gel comprising abiologically active agent such as clonidine and/or fluocinolone that isevenly distributed throughout the gel. The gel may be of any suitabletype, as previously indicated, and should be sufficiently viscous so asto prevent the gel from migrating from the targeted delivery site oncedeployed; the gel should, in effect, “stick” or adhere to the targetedtissue site. The gel may, for example, solidify upon contact with thetargeted tissue or after deployment from a targeted delivery system. Thetargeted delivery system may be, for example, a syringe, a catheter,needle or cannula or any other suitable device. The targeted deliverysystem may inject the gel into or on the targeted tissue site. Thetherapeutic agent may be mixed into the gel prior to the gel beingdeployed at the targeted tissue site. In various embodiments, the gelmay be part of a two-component delivery system and when the twocomponents are mixed, a chemical process is activated to form the geland cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×−10² to about 3×10⁵dynes/cm², 2×10⁴ to about 2×10⁵ dynes/cm² or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×−10² to about 2×10⁶ dynes/cm², 1×10⁵ to about 7×10⁵ dynes/cm² or2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer versus non-polymer). For example, in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, incorporation of chain transfer or chaincapping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000; or about 1,000to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 toabout 100,000; or about 20,000 to 50,000.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different MWs, a gel with a high molecular weight provides astronger matrix and the matrix takes more time to degrade. In contrast,a gel with a low molecular weight degrades more quickly and provides asofter matrix. In various embodiments, the gel has a molecular weight,as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2dL/g or from about 0.10 dL/g to about 0.40 dL/g. Other IV ranges includebut are not limited to about 0.05 to about 0.15 dL/g, about 0.10 toabout 0.20 dL/g, about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30dL/g, about 0.25 to about 0.35 dL/g, about 0.30 to about 0.35 dL/g,about 0.35 to about 0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45to about 0.50 dL/g, about 0.50 to about 0.70 dL/g, about 0.60 to about0.80 dL/g, about 0.70 to about 0.90 dL/g, and about 0.80 to about 1.00dL/g.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, or from about 15 cps to about 75 cps at room temperature. Thegel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides or a combination thereof. Synthetichydrogels include but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane or a combination thereof.

In various embodiments, rather than directly admixing the biologicallyactive agent or therapeutic agent into the gel, microspheres may bedispersed within the gel, the microspheres being loaded with abiologically active agent. In one embodiment, the microspheres providefor a sustained release of the biologically active agent. In yet anotherembodiment, the gel, which is biodegradable, prevents the microspheresfrom releasing the biologically active agent; the microspheres thus donot release the biologically active agent until they have been releasedfrom the gel. For example, a gel may be deployed around a target tissuesite (e.g., a nerve root). Dispersed within the gel may be a pluralityof microspheres that encapsulate the desired therapeutic agent. Certainof these microspheres degrade once released from the gel, thus releasingthe biologically active agent.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thebiologically active agent. In some situations, this may be desirable; inothers, it may be more desirable to keep the biologically active agenttightly constrained to a well-defined target site. The present inventionalso contemplates the use of adherent gels to so constrain dispersal ofthe therapeutic agent. These gels may be deployed, for example, in adisc space, in a spinal canal or in surrounding tissue.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device, e.g., a syringe, a gun drugdelivery device or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space. Typically, thetransforaminal approach involves approaching the intervertebral spacethrough the intervertebral foramina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes but is not limited to from about0.05 to about 1.655 (mm). The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include but are not limited to barium, bismuth, tantalum,tungsten, iodine, calcium, and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requiresindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including but not limited to gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot. The kit may include the drug depotdevice in a first compartment. The second compartment may include acanister holding the drug depot and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may include an agent for radiographic imaging. Each tool maybe separately packaged in a plastic pouch that is radiation sterilized.A cover of the kit may include illustrations of the implanting procedureand a clear plastic cover may be placed over the compartments tomaintain sterility.

In various embodiments, a method for delivering a biologically activeagent into a site of a patient is provided, the method comprisinginserting a cannula at or near a target tissue site and implanting thedrug depot at the target site beneath the skin of the patient andbrushing, dripping, injecting, or painting the gel in the target site tohold or have the drug depot adhere to the target site. In this way,unwanted migration of the drug depot away from the target site isreduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered at or near the target site. In thoseembodiments, where the drug depot is separate from the gel, first thecannula or needle can be inserted through the skin and soft tissue downto the site of injection and one or more base layer(s) of gel can beadministered to the target site. Following administration of the one ormore base layer(s), the drug depot can be implanted on or in the baselayer(s) so that the gel can hold the depot in place or reducemigration. If required, a subsequent layer or layers of gel can beapplied on the drug depot to surround the depot and further hold it inplace. Alternatively, the drug depot may be implanted first and then thegel placed around the drug depot to hold it in place. By using the gel,accurate and precise implantation of a drug depot can be accomplishedwith minimal physical and psychological trauma to the patient. The gelalso avoids the need to suture the drug depot to the target sitereducing physical and psychological trauma to the patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

When several drug depots are to be implanted, they are implanted in amanner that optimizes location, accurate spacing, and drug distribution.The drug depot can be delivered to any site beneath the skin, includingbut not limited to at least one muscle, ligament, tendon, shoulders,arms, the cervical part of the spine, cartilage, a spinal disc, a spinalforaminal space, near the spinal nerve root and the spinal canal.

In some embodiments, it is preferable to co-administer a biologicallyactive agent such as clonidine with an antagonist to counteractundesirable effects, for example, the blood pressure decrease that canbe caused by clonidine. Exemplary antagonists include but are notlimited to phentolamine, yohimbine, tolazoline and piperoxane.Additionally, compounds such as 5-fluorodeoxyuridine (FUDR) and 3,4dehydroprolene may also be included. These compounds may prevent orreduce glial and fibroblastic scar formation associated with some typesof surgenes.

The biologically active agent-based formulation of the presentapplication may be used as medicaments in the form of pharmaceuticalpreparations. The preparations may be formed in an administration with asuitable pharmaceutical carrier that may be solid or liquid and organicor inorganic, and placed in the appropriate form for parenteral or otheradministration as desired. As persons of ordinary skill are aware, knowncarriers include but are not limited to water, saline solution, gelatin,lactose, starches, stearic acid, magnesium stearate, sicaryl alcohol,talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol,polyalkylene glycols and other known carriers for medicaments.

In some embodiments, the biologically active agent is suitable forparenteral administration. The term “parenteral” as used herein refersto modes of administration that bypass the gastrointestinal tract, andinclude for example, intravenous, intramuscular, continuous orintermittent infusion, intraperitoneal, intrastemal, subcutaneous,intra-operatively, intrathecally, intradiscally, peridiscally,epidurally, perispinally, intraarticular injection or combinationsthereof. In some embodiments, the injection is intrathecal, which refersto an injection into the spinal canal (intrathecal space surrounding thespinal cord). An injection may also be into a muscle or other tissue.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,analgesic and anti-inflammatory combination) through a catheter near thetarget site, an implantable mini-pump that can be inserted at or nearthe target site, an implantable controlled release device or sustainedrelease delivery system that can release a certain amount of thebiologically active agent per hour or in intermittent bolus doses. Oneexample of a suitable pump for use is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gasthat provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of the pharmaceutical composition is controlled bya microprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously,continually, at specific times, or at set intervals between deliveries.

In various embodiments, the drug depot comprising the biologicallyactive agent can be made by combining a biocompatible polymer and atherapeutically effective amount of the biologically active agent orpharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), biologically activeagent(s) and optional materials including solution processing techniquesand/or thermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example, thebiocompatible polymer and/or biologically active agent. The particularsolvent species that make up the solvent system can also be selectedbased on other characteristics, including drying rate and surfacetension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: clonidine and/or fluocinolone,additional therapeutic agent(s) and other optional additives such asradiographic agent(s), etc. in dissolved or dispersed form. This resultsin a polymeric matrix region containing these species after solventremoval. In other embodiments, a solution containing solvent withdissolved or dispersed biologically active agent is applied to apre-existing polymeric region, which can be formed using a variety oftechniques including solution processing and thermoplastic processingtechniques, whereupon the biologically active agent is imbibed into thepolymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: clonidine,fluocinolone, optional additional therapeutic agent(s), radiographicagent(s), and so forth. The resulting mixture is then shaped into animplantable drug depot. The mixing and shaping operations may beperformed using any of the conventional devices known in the art forsuch purposes.

During thermoplastic processing, there exists the potential for thebiologically active agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, clonidine or fluocinolone may undergosubstantial degradation under ordinary thermoplastic processingconditions. Hence, processing is preferably performed under modifiedconditions, which prevent the substantial degradation of thebiologically active agent(s). Although it is understood that somedegradation may be unavoidable during thermoplastic processing,degradation is generally limited to 10% or less. Among the processingconditions that may be controlled during processing to avoid substantialdegradation of the biologically active agent(s) are temperature, appliedshear rate, applied shear stress, residence time of the mixturecontaining the biologically active agent, and the technique by which thepolymeric material and the biologically active agent(s) are mixed.

Mixing or compounding a biocompatible polymer with a biologically activeagent(s) and any additional additives to form a substantially homogenousmixture thereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the biologicallyactive agent among other reasons).

For example, in various embodiments, a biocompatible polymer ispre-compounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the biologically active agent, if it werepresent. This pre-compounded material is then mixed with a biologicallyactive agent under conditions of lower temperature and mechanical shear,and the resulting mixture is shaped into the biologically active agentcontaining drug depot. Conversely, in another embodiment, thebiocompatible polymer can be pre-compounded with the biologically activeagent under conditions of reduced temperature and mechanical shear. Thispre-compounded material is then mixed with, for example, aradio-opacifying agent, also under conditions of reduced temperature andmechanical shear, and the resulting mixture is shaped into the drugdepot.

The conditions used to achieve a mixture of the biocompatible polymerand biologically active agent and other additives will depend on anumber of factors including, for example, the specific biocompatiblepolymer(s) and additive(s) used, as well as the type of mixing deviceused.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a biologically active agent prone todegradation by heat and/or mechanical shear (e.g., clonidine), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The biologically active agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the biologically active agent(s). For instance, thebiologically active agent and premixed composition can bemixed/compounded using a twin screw extruder at substantially lowertemperatures (e.g., 100-105° C.), and using substantially reducedvolumetric output (e.g., less than 30% of full capacity, which generallycorresponds to a volumetric output of less than 200 cc/min). It is notedthat this processing temperature is well below the melting point ofclonidine because processing at or above these temperatures will resultin substantial biologically active agent degradation. It is furthernoted that in certain embodiments, the processing temperature will bebelow the melting point of all bioactive compounds within thecomposition, including the biologically active agent. After compounding,the resulting depot is shaped into the desired form, also underconditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or morebiologically active agent are premixed using non-thermoplastictechniques. For example, the biocompatible polymer can be dissolved in asolvent system containing one or more solvent species. Any desiredagents (for example, a radio-opacifying agent, a biologically activeagent, or both a radio-opacifying agent and a biologically active agent)can also be dissolved or dispersed in the solvents system. Solvent isthen removed from the resulting solution/dispersion, forming a solidmaterial. The resulting solid material can then be granulated forfurther thermoplastic processing (for example, extrusion) if desired.

As another example, the biologically active agent can be dissolved ordispersed in a solvent system, which is then applied to a pre-existingdrug depot (the pre-existing drug depot can be formed using a variety oftechniques including solution and thermoplastic processing techniques,and it can comprise a variety of additives including a radio-opacifyingagent and/or viscosity enhancing agent), whereupon the biologicallyactive agent is imbibed on or in the drug depot. As above, the resultingsolid material can then be granulated for further processing, ifdesired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), biologically active agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble biologically active agent such as clonidine isused, the immersion time should be held to a minimum to avoidunnecessary loss of biologically active agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, clonidine is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: clonidine, wherein the clonidine comprises from about 0.1wt. % to about 30 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, clonidine comprises fromabout 3 wt. % to about 20 wt. %, about 3 wt. % to about 18 wt. %, about5 wt. % to about 15 wt. % or about 7.5 wt. % to about 12.5 wt. % of theformulation. By way of an example, when using a 5%-15% clonidinecomposition, the mole ratio of clonidine to polymer would be fromapproximately 16-53 when using an approximately 80 kDalton polymer thathas a 267 grams/mole ratio. By way of another example, when using a5%-15% clonidine base in the composition, the mole ratio of clonidinebase to polymer would be from approximately 18-61 with a mole mass of230 g/mol.

In various embodiments, there is a pharmaceutical formulationcomprising: fluocinolone, wherein the fluocinolone comprises from about0.05 wt. % to about 25 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, fluocinolone comprises fromabout 2 or 3 wt. % to about 20 wt. %, about 3 wt. % to about 18 wt. %,about 5 wt. % to about 15 wt. % or about 7.5 wt. % to about 12.5 wt. %of the formulation.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt.% of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on the total weight of the depot and theremainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolide), poly(orthoester) or a combination thereof.The poly(lactic-co-glycolide) may comprise a mixture of polyglycolideand polylactide and in some embodiments, in the mixture, there is morepolylactide than polyglycolide. In various embodiments, there is 100%polylactide and 0% polyglycolide; 95% polylactide and 5% polyglycolide;90% polylactide and 10% polyglycolide; 85% polylactide and 15%polyglycolide; 80% polylactide and 20% polyglycolide; 75% polylactideand 25% polyglycolide; 70% polylactide and 30% polyglycolide; 65%polylactide and 35% polyglycolide; 60% polylactide and 40%polyglycolide; 55% polylactide and 45% polyglycolide; 50% polylactideand 50% polyglycolide; 45% polylactide and 55% polyglycolide; 40%polylactide and 60% polyglycolide; 35% polylactide and 65%polyglycolide; 30% polylactide and 70% polyglycolide; 25% polylactideand 75% polyglycolide; 20% polylactide and 80% polyglycolide; 15%polylactide and 85% polyglycolide; 10% polylactide and 90%polyglycolide; 5% polylactide and 95% polyglycolide; or 0% polylactideand 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide,there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size (e.g., clonidine) is fromabout 5 to 30 micrometers, however, in various embodiments ranges fromabout 1 micron to 250 microns may be used. In some embodiments, thebiodegradable polymer comprises at least 50 wt. %, at least 60 wt. %, atleast 70 wt. %, at least 80 wt. % of the formulation, at least 85 wt. %of the formulation, at least 90 wt. % of the formulation, at least 95wt. % of the formulation or at least 97 wt. % of the formulation. Insome embodiments, the at least one biodegradable polymer and theclonidine are the only components of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers.

In some embodiments, there is a pharmaceutical formulation comprisingclonidine, wherein the clonidine is in a mixture of clonidinehydrochloride and clonidine base and the mixture comprises from about0.1 wt. % to about 30 wt. % of the formulation and a polymer comprisesat least 70% of the formulation. In some embodiments, the polymer inthis formulation is polyorthoester.

In some embodiments, there is a pharmaceutical formulation comprisingfluocinolone, wherein fluocinolone comprises from about 0.05 wt. % toabout 25 wt. % of the formulation, and at least one biodegradablepolymer, wherein the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) or poly(orthoester) or a combinationthereof, and the at least one biodegradable polymer comprises at least80 wt. % of the formulation.

In some embodiments, the formulation comprises a drug depot thatcomprises a biodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester can be obtained from A.P.Pharma, Inc. (Redwood City, Calif.) or through the reaction of abis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there are methods for weight control comprisingadministering a biologically active agent composition to an organism,wherein the biologically active agent composition comprises from about0.1 wt. % to about 30 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, the loading is from about 1wt. % to about 25 wt. %, or about 5 wt. % to about 10 wt. %. In someembodiments, the loading is from about 10 wt. % to about 20 wt. %.

In some embodiments, there is a higher loading of clonidine orfluocinolone, e.g., at least 20 wt. %, at least 30 wt. %, at least 40wt. %, at least 50 wt. %, at least 60 wt. %, at least 70 wt. %, at least80 wt. % or at least 90 wt. %.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)of drug depots comprising the pharmaceutical formulations may be placedaround the target site such that the target tissue site falls within aregion that is either between the formulations when there are two, orwithin an area whose perimeter is defined by a set of plurality offormulations.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.50 mm and a length of 4 mm. It should be noted thatparticle size may be altered by techniques such as mort and pestle,jet-drying or jet milling.

Fluocinolone is available from various pharmaceutical manufacturers. Thedosage of fluocinolone may be from approximately 0.0005 to approximately100 μg/day. Additional dosages of fluocinolone include fromapproximately 0.0005 to approximately 50 μg/day; approximately 0.0005 toapproximately 25 μg/day; approximately 0.0005 to approximately 10μg/day; approximately 0.0005 to approximately 5 μg/day; approximately0.0005 to approximately 1 μg/day; approximately 0.005 to approximately0.75 μg/day; approximately 0.0005 to approximately 0.5 μg/day;approximately 0.0005 to approximately 0.25 μg/day; approximately 0.0005to approximately 0.1 μg/day; approximately 0.0005 to approximately 0.075μg/day; approximately 0.0005 to approximately 0.05 μg/day; approximately0.001 to approximately 0.025 μg/day; approximately 0.001 toapproximately 0.01 μg/day; approximately 0.001 to approximately 0.0075μg/day; approximately 0.001 to approximately 0.005 μg/day; approximately0.001 to approximately 0.025 μg/day; and 0.002 to approximately 0.025μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 15 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to approximately10 μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 5 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to 2.5 μg/day. Insome embodiments, the amount of fluocinolone is between 40 and 600μg/day. In some embodiments, the amount of fluocinolone is between 200and 400 μg/day. Dosing formulations may be prepared to contain asufficient amount of the active ingredient to enable the desired aboutof compound to be release over the desired amount of time.

In some embodiments, there is sufficient fluocinolone such that thefluocinolone is released at a rate of 2-3 μg per day for a period of atleast three days. In some embodiments, this release rate continues for,at least ten days, at least fifteen days, at least twenty-five days, atleast thirty days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days.

For some embodiments, 300-350 micrograms of fluocinolone as formulatedwith a biopolymer are implanted into a person at or near a target tissuesite. If fluocinolone is implanted at multiple sites that triangulatethe target site then in some embodiments, the total amount offluocinolone at each site is a fraction of the total 300-350 micrograms.For example, one may implant a single does of 324 micrograms at onesite, or two separate doses of 162 micrograms at two sites, or threeseparate dose of 108 micrograms at three sites that triangulate thetissue site. It is important to limit the total dosage to an amount lessthan that which would be harmful to the organism. However, in someembodiments, although when there are a plurality of sites each site maycontain less than the total does that might have been administered in asingle application, it is important to remember that each site willindependent have a release profile, and the biopolymers' concentrationand substance should be adjusted accordingly to ensure that the sustainrelease occurs over sufficient time.

In some embodiments where clonidine is the biologically active agent,clonidine is released at a rate of 2-3 μg per day for a period of atleast three days. In some embodiments, this release rate continues forat least ten days, at least fifteen days, at least twenty-five days, atleast fifty days, at least ninety days, at least one hundred days, atleast one-hundred and thirty-five days, at least one-hundred and fiftydays or at least one hundred and eighty days. For some embodiments,300-425 micrograms of clonidine as formulated with a biopolymer areimplanted into a person at or near a target tissue site. If clonidine isimplanted at multiple sites that triangulate the target site, then insome embodiments, the total amount of clonidine at each site is afraction of the total 300-425 micrograms. For example, one may implant asingle dose of 324 micrograms at one site, or two separate doses of 162micrograms at two sites, or three separate doses of 108 micrograms atthree sites that triangulate the tissue site. It is important to limitthe total dosage to an amount less than that which would be harmful tothe organism. However, in some embodiments, although when there are aplurality of sites each site may contain less than the total dose thatmight have been administered in a single application, it is important toremember that each site will independently have a release profile, andthe biopolymers' concentration and substance should be adjustedaccordingly to ensure that the sustain release occurs over sufficienttime.

The dosage may be from approximately 0.0005 to approximately 960 μg/day.Additional dosages of clonidine include from approximately 0.0005 toapproximately 900 μg/day; approximately 0.0005 to approximately 500μg/day; approximately 0.0005 to approximately 250 μg/day; approximately0.0005 to approximately 100 μg/day; approximately 0.0005 toapproximately 75 μg/day; approximately 0.001 to approximately 70 μg/day;approximately 0.001 to approximately 65 μg/day; approximately 0.001 toapproximately 60 μg/day; approximately 0.001 to approximately 55 μg/day;approximately 0.001 to approximately 50 μg/day; approximately 0.001 toapproximately 45 μg/day; approximately 0.001 to approximately 40 μg/day;approximately 0.001 to approximately 35 μg/day; approximately 0.0025 toapproximately 30 μg/day; approximately 0.0025 to approximately 25μg/day; approximately 0.0025 to approximately 20 μg/day; approximately0.0025 to approximately 15 μg/day; approximately 0.0025 to approximately10 μg/day; approximately 0.0025 to approximately 5 μg/day; andapproximately 0.0025 to approximately 2.5 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 10 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 5μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 2.5 μg/day. In some embodiments,the amount of clonidine is between 40 and 600 μg/day. In someembodiments, the amount of clonidine is between 200 and 400 μg/day.

In some embodiments, the therapeutically effective dosage amount (e.g.,clonidine dose) and the release rate profile are sufficient for weightcontrol and/or reduce, prevent or treat obesity for a period of at leastone day, 1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12 days; 3-14 days,7-10 days, 7-14 days, 7-21 days, 7-30 days, 7-50 days, 7-90 days, 7-140days, 14-140 days, 3 days to 135 days, 3 days to 180 days, or 3 days to6 months or 1 year or longer.

In some embodiments, the drug depot is designed for a bolus dose orburst dose within 1, 2 or 3 days after implantation to provide animmediate release of the drug for weight control followed by a sustainedrelease of the drug for a longer period for weight control.

In some embodiments, the drug depot is administered parenterally, e.g.,by injection. In some embodiments, the injection is intrathecal, whichrefers to an injection into the spinal canal (intrathecal spacesurrounding the spinal cord). An injection may also be into a muscle orother tissue. In other embodiments, the drug depot is administered byplacement into an open patient cavity during surgery.

In one exemplary dosing regimen, a rat may be provided with sufficientclonidine in a biodegradable polymer to provide sustain release of 0.240μg/day for 135 days. The total amount of clonidine that is administeredover this time period would be approximately 32.4 μg. In anotherexemplary dosing regimen, a human is provided with sufficient clonidinein a biodegradable polymer to provide sustain release of 2.4 μg/day for135 days. The total amount of clonidine that is administered over thistime period would be approximately 324 μg.

When using a plurality of pellets, the pellet number is based on theamount of drug loading into a pellet of appropriate size (i.e., 0.5 mmdiameter×4 mm length) and how much drug is needed (e.g., approximately325 μg clonidine (3 pellets)). In some embodiments, there is a polymerthat releases a bolus amount of compound over the first few (˜5) daysbefore it settles down and releases 2.5 mg/day for 135 days. Anexemplary formulation is 5 wt. % clonidine, 100 DL 5E (LakeshoreBiomaterials, Birmingham, Ala.).

In some embodiments, the polymer depots of the present invention enableone to provide efficacy of the active ingredient that is equivalent tosubcutaneous injections that deliver more than 2.5 times as much drug.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

Examples

The examples below with respect to certain formulations comprisingclonidine as the biologically active agent show certain particularlyadvantageous results wherein the initial burst is not too large (i.e.,not more than 7% of the load drug in the first five days) and the dailydose is approximately 2.4 μg/day±0.5 μg/day for 135 days. See e.g.,FIGS. 12, 13, 14 and 19. These figures further demonstrate that withrespect to clonidine, a drug loading of 5 wt. % to 8 wt. % providesadvantageous results.

Example 1 Fluocinolone Formulation Testing

FIG. 1 provides a table fourteen formulations that contain fluocinoloneas the biologically active agent and excipients, including oneformulation that contains no excipients. FIG. 2 provides a graph of acumulative API released percentage for the formulations of FIG. 1, someof which have been irradiated. (Note that in the legend, the percentageof the FL (fluocinolone) is rounded off). FIG. 3 provides the calculateddaily micrograms released for the last six formulations in FIG. 1.

The In-Vitro Elution Studies were carried out at 37° C. inphosphate-buffered saline with 0.5% SDS (pH 7.4). Briefly, the rods(n=3) were weighed prior to immersion in 10 mL of PBS. At regular timeintervals, the PBS was removed for analysis and replaced with 10 mL offresh PBS. The PBS-elution buffer was analyzed for fluocinolone contentusing UV-Vis spectrometry.

FIG. 4 shows various formulations which were made and comprisefluocinolone as the biologically active agent. The elution profiles forthese formulations ranged from 30 days to 100 days and are shown inFIGS. 35 and 36.

Example 2

Purpose: The purpose of this study was to evaluate the in vivo drugelution rate from a biodegradable polymer dosage form comprisingfluocinolone as the biologically active agent and compare it topreviously generated in vitro data.

Experimental Methods Summary: Twenty four Sprague Dawley rats wereutilized in this study. Every rat was implanted with two or threesubcutaneous (SQ) implants (2 sites per animal). Group 1 receivedactive-loaded (i.e., fluocinolone-loaded) polymer. Group 2 receivedunloaded (control) polymer (3 sites per animal).

The polymer pellets were implanted by making a dorsal midline skinincision (approximately 2 cm long) and creating a lateral SQ pocket(approximately 1 cm×1 cm) by blunt dissection. The pellets weredeposited with a forceps. The skin incision was closed using skinstaples.

The rats were allowed to recover from the implant procedure, andsacrificed on Days 3, 7, 14, 21, 28, and 66 according to a predeterminedschedule. At necropsy, the remaining dosage form was identified, andsome portion was recovered. The retrieved portion of the dosage form wasweighed and analyzed for drug content. At termination, a blood samplewas collected via cardiac puncture (approximately 1 mL) and transferredto an EDTA tube. Plasma in EDTA was isolated for future drug analysis.Table 1 below summarizes the fluocinolone depots used and the testparameters.

TABLE 1 # of Pellet Test Dimensions Sites Strain Formul Dosage (L × D)per # of Animal Total # of Gp of Rat ID Form Pellet # (mm) AnimalSacrifices Sacrifices^(a) Animals 1 N 13395- *20% 6 0.7 × 0.7 2 6 3 1863-6 Fluocin. in 85/15 PLGA + 10% mPEG 2 N 13395- 85/15 6   4 × 0.75 3 23 6 68-5 PLGA + 10% mPEG N = normal ~300 g Spague-Dawley ^(a)Group 1 wassacrificed at: 3, 7, 14, 21, 28, and 56 days post-implant (Implant = Day0) Group 2 was sacrificed at: 28 and 56 days post-implant (Implant = Day0)

FIG. 37 shows in vitro daily release profiles and in vivo daily plasmalevel profiles of 12 depots (6 depots implanted in two sites) containingfluocinolone. This dosage is approximately double the amount of normalhuman doses (6 depots would be used in humans). An initial burst orimmediate release of fluocinolone was observed for about 3 days,achieving over 1.5 to over 3.5 mcg per day for the in vitro testing. Thein vivo plasma levels had an initial burst in about 3 days of about400-600 pg/ml in the plasma, which is relatively low considering 12depots were implanted. After about 3 days, an in vitro daily drugrelease from the depots was between about 0.01 and about 2.5 mcg/day ina consistent release for over 100 days. The in vivo plasma levels offluocinolone were also consistent after 30 days achieving plasma levelsin the 150 to 250 picograms/ml range.

Another formulation comprising fluocinolone as the biologically activeagent was prepared. The formulation included 20% fluocinolone, 70% PLGA8515 and 10% mPEG. The fluocinolone drug load, content uniformity anddrug purity for pellets from this formulation are shown in Table 2below.

TABLE 2 Ave Dose Wt. Drug 5 Pellets Content Content % Drug % Drug Purity% Formulation (mg) mcg/pellet Uniformity Load Theoretical Peak AreaPre-Sterile 3.14 625 10.4% 19.9% 99.5% 99.0% Post- 3.11 612 13.9% 19.7%98.4% 98.9% Gamma

The elution profiles for these pellets are shown in FIG. 38. Thefluocinolone drug depot had about 20% to 25% of fluocinolone eluted fromthe depot in vivo for a period of 30 days. In vivo drug depots weremeasured by explanting the pellet and measuring the wt. % drug elutedfrom the depot. In vitro drug elution was measured using PBS or PBS andSDS and measuring the wt. % cumulative elution. The in vitro elutioncorrelated with in vivo elution where there was an initial burst effectand immediate release of the drug within the first 3 days and then aconsistent sustained release for up to 57 days or 30 days, respectively.

Example 3 Formulation Testing

A number of formulations comprising clonidine as the biologically activeagent were prepared in which the polymer type, drug load, excipient(including some formulations in which there was no excipient), pelletsize and processing were varied. These formulations are described belowin Table 3, Table 4 and Table 5. A number of tests were performed onthese formulations, including in vitro release tests in which the numberof micrograms released was measured, as well as the cumulativepercentage release of clonidine. The results of these tests appear inFIGS. 5-34.

FIG. 5 is a graphic representation of a study of the cumulative releaseby percentage of clonidine HCl sterilized formulations. In FIG. 5, theformulations (first three of Table 3) contained: 8.1 wt. % clonidine,the remainder 100 DL 5E (the inherent viscosity of the 100 DL was0.45-0.55 and had an ester end group), or 7.2 wt. % clonidine, theremainder 100 DL 7E (the inherent viscosity of the 100 DL was 0.60-0.80and had an ester end group) or 5 wt. % clonidine, the remainder 100 DL5E (the inherent viscosity of the 100 DL was 0.45-0.55 and had an esterend group). The formulations with the higher drug loads released thefastest over 70 days, with a cumulative release of 45% and 80%. Theformulation with 5% clonidine drug load released drug the longest forover 160 days and had a cumulative release of 95% of the drug.

FIG. 6 is an in vitro graphic representation of studies of thepercentage daily release profiles of sterilized clonidine formulationsof FIG. 5 (first three of Table 5) and their cumulative average dailyrelease of the three formulations in micrograms per day. Each drug depothad an initial burst effect with a release of clonidine over 50 mcg forthe first day. These calculations are based on 3 pellets implanted(which would approximate the dose of clonidine in humans). The pelletsranged in size from 0.5 mm to about 1 mm in diameter and 3-4 mm inlength, which would be small enough to place in a needle. Theformulations with the higher drug loads released the fastest over 70days, where the drug dose released was about 5 mcg to about 0.1 mcg/dayafter about the first 30 days and the formulation with the lowest drugload of about 5% clonidine released the longest for a period of over 160days, where the release was consistently between about 5 mcg to 0.1mcg/day after about day 30. The target daily dose was 2.4 mcg/day andthe formulation with the 5% clonidine drug load came closest to thistarget daily dose.

In vitro elution studies were carried out at 37° C. inphosphate-buffered saline (PBS, pH 7.4). The rods (n=3) were weighedprior to immersion in 5 mL of PBS. At regular time intervals, the PBSwas removed for analysis and replaced with 5 mL of fresh PBS. ThePBS-elution buffer was analyzed for clonidine content using UV-Visspectrometry.

TABLE 3 Drug Pellet Size (L × Load Dia; mm) or Notebook ID Polymer Type(Wt. %) Excipient Description Processing 13335-60-1 8515 DLG 7E 10 N/A0.75 × 0.75 Melt extrusion, co-spray dried drug/polymer 13335-60-2 8515DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-60-38515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, hand ground drug13335-60-4 8515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, hand grounddrug, spray dried polymer 13335-60-5 8515 DLG 7E 10 N/A 0.75 × 0.75 Meltextrusion w/ recycle loop, hand ground drug 13335-65-1 8515 DLG 7E 5 N/A 3.0 × 0.75 Melt extrusion, spray dried drug 13335-65-2 8515 DLG 7E 10N/A  1.5 × 0.75 Melt extrusion, spray dried drug 13335-65-3 8515 DLG 7E20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-65-4 100 DL 7E5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-65-5 100 DL 7E10 N/A  1.5 × 0.75 Melt extrusion, spray dried drug 13335-65-6 100 DL 7E20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-97-1 8515 DLG7E 7.5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-97-2 100DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-97-3 8515DLG 7E 5  10% mPEG  3.0 × 0.75 Melt extrusion, spray dried drug13335-97-4 100 DL 7E 5  10% mPEG  3.0 × 0.75 Melt extrusion, spray drieddrug 13699-1-1 100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray drieddrug 13699-16-1 8515 DLG 7E 10 N/A  1.5 × 0.75 Melt extrusion, spraydried drug 13699-16-2 9010 DLG 7E 10 N/A  1.5 × 0.75 Melt extrusion,spray dried drug 13699-16-3 9010 DLG 7E 5 N/A  3.0 × 0.75 Meltextrusion, spray dried drug 13699-16-4 8515 DLG 7E 5   5% mPEG  3.0 ×0.75 Melt extrusion, spray dried drug 13699-16-5 8515 DLG 7E 5 2.5% mPEG 3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-1 8515 DLG 7E 5  1% MgO  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-4 8515DLG 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-5 100DL 7E 5  10% 5050  3.0 × 0.75 Melt extrusion, spray dried drug DLG 6E13699-20-6 100 DL 7E 5  10% 5050  3.0 × 0.75 Melt extrusion, spray drieddrug DLG 1A 13699-20-7 8515 DLG 10 N/A  1.5 × 0.75 Melt extrusion, spraydried drug Purac 13699-20-8 8515 DLG 7E 5 N/A  3.0 × 0.75 Melt extrusion2X, spray dried drug 13699-28-1 8515 DLG 7.5 N/A  3.0 × 0.75 Meltextrusion, spray dried drug Purac 13699-28-2 8516 DLG 12.5 N/A  2.0 ×0.75 Melt extrusion, spray dried drug Purac 13699-28-3 100 DL 7E 5 N/A 3.0 × 0.75 Melt extrusion, spray dried drug 13699-31-1 8515 DLG 7E 10N/A N/A heat press, spray dried drug 13699-31-2 8515 DLG 7E 10 N/A N/Aheat press, spray dried drug 13699-31-3 8515 DLG 7E 10 N/A N/A heatpress, spray dried drug 13699-31-4 8515 DLG 7E 10 N/A N/A Meltextrusion, spray dried drug 12702-13-4-a 1,6-Hexanediol/ 10 N/A 3 × 3Melt extrusion tCHDM 12702-13-4-b 75/25 PLGA 10 N/A 3 × 3 Melt extrusion12702-68-12 75/25 PLGA 5 mPEG 1 × 1 Melt extrusion 12702-68-13 75/25PLGA 5 TBO-Ac 1 × 1 Melt extrusion 12702-72-1 75/25 PLGA 5 mPEG 1 × 1Melt extrusion 12702-80-7 75/25 PLGA 10 mPEG 0.75 × 0.75 Melt extrusion12702-80-8 75/25 PLGA 15 mPEG 0.75 × 0.75 Melt extrusion 13395-3-1 85/15PLGA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-3-2 85/15 PLGA 15 mPEG0.75 × 0.75 Melt extrusion 13395-3-3 85/15 PLGA 5 mPEG 0.75 × 0.75 Meltextrusion 13395-15 85/15 PLGA 15 mPEG 0.75 × 0.75 Melt extrusion13395-20-1 85/15 PLGA 5 Span-85 0.75 × 0.75 Melt extrusion 13395-20-285/15 PLGA 5 Pluronic- 0.75 × 0.75 Melt extrusion F127 13395-20-3 85/15PLGA 5 N/A 0.75 × 0.75 Melt extrusion 13395-21-1 D,L-PLA 5 mPEG 0.75 ×0.75 Melt extrusion 13395-21-2 85/15 PLGA 5 TBO-Ac 0.75 × 0.75 Meltextrusion 13395-24-1 85/15 PLGA 5 Span-65 0.75 × 0.75 Melt extrusion13395-27-1 85/15 PLGA 10 N/A 0.75 × 0.75 Melt extrusion 13395-27-2 85/15PLGA 15 N/A 0.75 × 0.75 Melt extrusion 13395-27-3 85/15 PLGA 10 Span-650.75 × 0.75 Melt extrusion 13395-27-4 85/15 PLGA 10 TBO-Ac 0.75 × 0.75Melt extrusion 13395-27-5 85/15 PLGA 10 Pluronic 0.75 × 0.75 Meltextrusion F127 13395-34-2 D,L-PLA 10 N/A 0.75 × 0.75 Melt extrusion13395-34-3 D,L-PLA 10 TBO-Ac 0.75 × 0.75 Melt extrusion 13395-34-4D,L-PLA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-42-1 DL-PLA/PCL 10 N/A0.75 × 0.75 Melt extrusion 13395-42-2 DL-PLA/PCL 15 N/A 0.75 × 0.75 Meltextrusion

TABLE 4 Drug Load Pellet Size (L × Dia; mm) Notebook ID Polymer Type(Wt. %) Excipient or Description Processing 13335-73-1 POE 58 10 N/A 1.5 × 0.75 Melt extrusion 13335-73-2 POE 58 20 N/A 0.75 × 0.75 Meltextrusion 13335-73-3 POE 60 10 N/A  1.5 × 0.75 Melt extrusion 13335-73-4POE 60 20 N/A 0.75 × 0.75 Melt extrusion 13699-1-2 POE 58 10 N/A 4 − 1.5× 0.75  Melt extrusion 13699-1-3 POE 58 20 N/A 1 − 0.75 × 0.75 Meltextrusion 12702-23 tCHDM (100) 25 N/A Microspheres Double emulsion12702-26 tCHDM/DET 4.2 N/A Microspheres Double emulsion (70/30) 12702-5475/25 PLGA 20 N/A Microspheres Double emulsion 12702-68-9 75/25 PLGA 5mPEG 3 × 3 Melt extrusion 12702-68-10 75/25 PLGA 5 TBO-Ac 3 × 3 Meltextrusion 12702-87 75/25 PLGA 15 mPEG Mixer-Molder 12702-90 85/15 PLGA17 N/A Mixer-Molder 12702-78-1 Polyketal 7 N/A 2 × 3 Melt extrusion(12833-14-1) 13395-14 50/50 PLGA 10 mPEG N/A Melt extrusion (2A)13395-17-1 POE (13166- 5 N/A 1.5 × 1.5 Melt extrusion 75) 13395-17-2 POE(13166- 5 N/A 1.5 × 1.5 Melt extrusion 77) 13395-47-1 DL-PCL 10 N/A 1.3× 1.3 Melt extrusion 13395-50 DL-PCL 10 N/A 1.3 × 1.3 Melt extrusion; w/solvent prep 13395-51 D,L-PLA 10 mPEG N/A Melt extrusion

TABLE 5 Drug Load Notebook ID Polymer Type (Wt. %) Processing 00178-23100 DL 5E 8.1 Melt extrusion, hand mixed 00178-15 100 DL 7E 7.2 Meltextrusion, hand mixed 00178-35 100 DL 5E 5 Melt extrusion, hand mixed00178-16 100 DL 7E 10.2 Melt extrusion, hand mixed 00178-21 8515 DL 7E7.3 Melt extrusion, hand mixed 00178-36 100 DL 7E 5 Melt extrusion, handmixed 00178-44 100 DL 7E 5.1 Dissolved in glacial acetic acid, freezedried, melt extrusion 00178-45 100 DL 7E 4.5 Drug and polymer blend,prepared in N2 environment, melt extrusion 00178-45-C 100 DL 7E 4.5Formulation 00178-45 with EtOAc coating 00178-63 100 DL 7E 9.4 Meltextrusion 00178-08 100 DL 7E 21.4 melt extrusion, no reduction in drugparticle size 00178-11 100 DL 7E 7.9 melt extrusion, no reduction indrug particle size 00178-12 100 DL 7E 11.7 melt extrusion, no reductionin drug particle size 00178-22 8515 DL 7E 8.3 melt extrusion 00178-24100 DL 5E 10.1 melt extrusion 00178-23-C 100 DL 5E 8.1 Formulation00178-23 with EtOAc coating 00178-23-PC 100 DL 5E 8.1 Formulation00178-23 with polymer solution coating 00178-35-C 100 DL 5E 5Formulation 00178-35 with EtOAc coating 00178-36-C 100 DL 7E 5Formulation 00178-36 with EtOAc coating 00178-72 100 DL 7E 4.5 DoubleExtrusion (20% diluted to 5%) 00178-73 100 DL 7E 8.7 Double Extrusion(20% diluted to 10%) 00178-74 6353 DLG 7E 7.3 Melt extrusion, hand mixed00178-71 6535 DLG 7E 5.3 Melt extrusion, hand mixed 00178-75 6535 DLG 7E3.3 Melt extrusion, hand mixed 00178-76-R1 100 DL 7E core with 7.76coaxial extrusion, 4 different coating thicknesses 100DL 5E Coating00178-76-R2 100 DL 7E core 6.92 coaxial extrusion, 4 different coatingthicknesses with 100DL 5E coating 00178-76-R3 100 DL 7E core 6.76coaxial extrusion, 4 different coating thicknesses with 100DL 5E coating00178-76-R4 100 DL 7E core 8 coaxial extrusion, 4 different coatingticknesses with 100DL 5E coating 00178-79-R1 100 DL 5E core with 12.1coaxial extrusion, thin coat 100DL 5E coating 00178-80-R1 100 DL 5E corewith 7.54 coaxial extrusion, different coating thicknesses 100DL 5Ecoating 00178-80-R3 100 DL 5E core with 8.9 coaxial extrusion, differentcoating thicknesses 100DL 5E coating 00178-80-R4 100 DL 5E core with10.0 coaxial extrusion, different coating thicknesses 100DL 5E coating00178-77 100 DL 5E 5.2 repeat of 178-35 (1.0 mm diameter) 00178-78 100DL 5E 5.1 repeat of 178-35 (0.8 mm diameter) 00178-81 100 DL 5E 7.2repeat of 178-23 00178-87 100 DL 5E 5.0 Repeat of 178-35 (1.0 mm diam)00178-90 100 DL 5E 5 Repeat 178-35, mechanical mixing, single screw meltextrusion (0.8 mm and 1.0 mm diameter) 00178-91-R1 100 DL 5E core with3.5 Coaxial extrusion, thick coating 100DL 5E coating 00178-91-R6 100 DL5E core with 7.4 Coaxial extrusion, thin coating 100DL 5E coating00178-93-R3 100 DL 5E core with 5 Coaxial extrusion, mechanical mixing,thin coating layer 100DL 7E coating 00178-93-R4 100 DL 5E core with 3.8Coaxial extrusion, mechanical mixing, thick coating layer 100DL 7Ecoating

The codes within the table for the polymer are explained as follows. Thefirst number or numbers refer to the monomer mole percentage ratio ofDL-lactide (e.g., polylactide) to glycolide (e.g., poly-glycolide). Theletter code that follows the first number refers to the polymer(s) andis the polymer identifier. The second number, which follows the lettercode for the polymer, is the target IV designator and is 10 times themidpoint of a range in dl/g. The meanings of certain IV designators arereflected in Table 6.

Table 6 IV Target Designator IV Range 0.05 - 0.15 0.10 - 0.20 0.15 -0.25 0.20- 0.30 0.25- 0.35 0.30- 0.40 0.35- 0.45 0.40- 0.50 0.45- 0.550.50- 0.70 0.60- 0.80 0.70 - 0.90 0.80- 1.0

The final letter within the code of the polymer is the end groupdesignator. For example, “E” refers to an ester end group, while “A”refers to an acid end group.

By way of example, 100 DL7E is a polymer that has an inherent viscosityof 0.60-0.80 dL/g. It contains 100% poly(DL-lactide) that has ester endgroups. It is available from Lakeshore Biomaterials, Birmingham, Ala.

FIG. 7 is a graphic representation of clonidine HCl release for variousformulations (identified in Table 5) as measured by the cumulativeclonidine released percentage. In FIG. 7, the formulations contained: 10wt. % clonidine, the remainder 100 DL 7E (the inherent viscosity of the100 DL was 0.60-0.80 and had an ester end group) or 7 wt. % clonidine,the remainder 8515 DLG or 5 wt. % clonidine, the remainder 100 DL 7E(the inherent viscosity of the 100 DL was 0.60-0.80 and had an ester endgroup), or 10 wt. % clonidine, the remainder 100 DL 7E (the inherentviscosity of the 100 DL was 0.60-0.80 and had an ester end group) andthe pellets had small diameters of 0.5 mm. The clonidine formulationwith the 10% drug load had a faster release also because it had asmaller diameter, but increased surface area, which allowed a fasterdrug release. This formulation was dispersed better in the polymer asindicated by the fine mixing legend. The 10% clonidine formulation thatwas thicker in diameter and was less dispersed throughout the polymerhad a slower release profile. The lower drug load formulation of 7% hadthe longest release period of over 60 days. In general, increasing thedrug load was found to cause a more rapid release of the drug while thelower drug loads were found to produce a more sustained release effect.All formulations had an initial burst release within 1-2 days of between5% and 35% cumulative clonidine release.

FIG. 8 is a graphic representation of the cumulative in vitro releaseprofile for certain clonidine formulations (identified in Table 5)having different processing. The depots had PLG polymer coatings (polysoln), solvent coating with ethyl acetate (EtOAC), glacial acetic acid(glacial HoAc), or was processed in a nitrogen environment and coatedwith ethyl acetate as indicated in the legend. The coatings can beapplied by methods known in the art (e.g., spray coating, dip coating,etc.). The solvents used to coat the depot can be solvents known in theart, for example, acetone, methyl chloride, chloroform, EtOAC, etc. Thecoatings produced a release from 12 to 35 days with the fastest release(over 100%) in the formulation that was placed in a nitrogenenvironment. The longest release was observed for the formulation withthe polymer coating and high drug load of clonidine 7 wt. % where drugwas released for over 35 days.

FIG. 9 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations produced as indicatedin Table 5. The slowest release was seen for clonidine formulations thatwere double extruded, where a first batch was mixed and then extrudedand then that batch was mixed again and extruded to form the doubleextruded composition. These formulations had a slower polymerdegradation and drug release at about day 30 when compared toformulations that were not double extruded. The formulations with theDLG 7E (the inherent viscosity of the 100 DL was 0.60-0.80 and had anester end group) polymer had a rapid release and a second burst aboutday 30.

FIG. 10 is a graphic representation of certain calculated daily releasemeasurements of the clonidine formulations shown in FIG. 9 with 2/3/4pellet doses. The slowest release was seen for clonidine formulationsthat were double extruded, where a first batch was mixed and thenextruded and then that batch was mixed again and extruded to form thedouble extruded depot. These formulations had a slower polymerdegradation and drug release at about day 30, when compared toformulations that were not double extruded. The formulations with theDLG 7E (the inherent viscosity of the 100 DL was 0.60-0.80 and had anester end group) polymer had a rapid release and a second burst aboutday 30. All formulations had an initial burst release on day one fromabout 10 mcg-50 mcg and the daily release ranged from 0.5 mcg to 20mcg/day over about 48 days. The formulations that were not doubleextruded had a second initial burst at around day 25 to day 35 asindicated by the large peaks. These formulations did not have polymercoatings on the depot and, thus, had high initial bursts ranging from 30mcg-50 mcg.

FIG. 11 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses produced as indicated in Table5. Each pellet (drug depot) had an inner core of drug and polymer and anouter coating with varying degrees of thickness (a thick coating isabout 50˜100 microns and a thin coating is about 5 microns to about ˜20microns). The thinnest coating (about 20 microns) had the highestinitial burst ranging from about 9-14 mcg, which was much less than theuncoated depots from FIG. 10. The formulations in FIG. 11 were designedto decrease the initial burst with the outer coating. In general, thethicker the coating on the polymer drug core, the slower the drugrelease from the depot.

FIG. 12 is a graphic representation of the cumulative in vitro releaseprofile of clonidine from certain coaxial formulations (Table 5). Theformulations containing clonidine loads having 7.76 wt. %, 6.92 wt. %,6.76 wt. %, or 8.0 wt. % had a polymer and drug core with no outercoating. In general, with respect to these 4 formulations, the higherthe drug loads, the faster the drug release and more release of the drugfrom the depot. For example, the drug depot having an 8.0 wt. % drugload (the highest load in the core group) released about 90 wt. % of thedrug from the depot at about 70 days. In the second group, theformulations containing clonidine loads having 12.1 wt. %, 7.6 wt. %,8.9 wt. % or 10.0 wt. % had a polymer and drug core with an outercoating to delay release. The higher the drug load, the thinner thecoating and the lower the drug load, the thicker the coating. Theseresults show that by varying the drug load, changing the polymer from DL7E (the inherent viscosity of the 100 DL was 0.60-0.80 and had an esterend group) to DL 5E (the inherent viscosity of the 100 DL was 0.45-0.55and had an ester end group) and changing the coating thickness (a thickcoating is about 50˜100 microns and a thin coating would be 5 to about˜20 microns), the release profile of the drug depot was changed whereinthe higher drug loads (12.1 wt. % and 10 wt. %) had a higher %cumulative release and the lower drug loads (8.9 wt. % and 7.6 wt. %)had a lower % cumulative release.

FIG. 13 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations in Table 5. Theformulations contained 5 wt. % clonidine drug loads and the drug depotwas either 1 mm or 0.8 mm. One formulation had a drug load of 7 wt. %.None of the formulations had a polymer coating. In general, the smallerthe diameter of the pellet, the more rapid release of the drug from thedrug depot as the smaller diameter pellets had increased surface areawhich can lead to a higher % cumulative release of drug from the drugdepot.

FIG. 14 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations of FIG. 13 that didnot have coatings on them. All formulations had a high initial burstrelease on day one from about 28 mcg-32 mcg and daily release rangedfrom 0.5 mcg to 4 mcg/day over about 75-95 days. There was no coating onthese pellets, which lead to a high initial burst. All formulations hadconsistent release after the initial burst period.

FIG. 15 is a graphic representation of the cumulative release percentageof clonidine for certain formulations in Table 5. The formulationscontaining clonidine loads having 3.54 wt. %, 7.38 wt. %, 5.0 wt. %, or3.8 wt. % had polymer and drug core and polymer DL coating. The polymerfor the drug core was 100 DL 5E (the inherent viscosity of the 100 DLwas 0.45-0.55 and had an ester end group) and some had this polymer forthe coating (sheath) as indicated in the legend. Others had the drugcore polymer as DL 5E (the inherent viscosity of the DL was 0.45-0.55and had an ester end group) and the polymer coating (sheath) on the coreas indicated in the legend was DL 7E (the inherent viscosity of the DLwas 0.60-0.80 and had an ester end group). The thinnest coating andhighest drug load (7.38 wt. % clonidine) had the fastest release andthicker coating and lowest drug load (3.54 wt. % clonidine) had theslower drug release considering both groups had the same polymer andcoating 100 DL 5E (a thick coating is about 50˜100 microns and a thincoating would be 5 to about ˜20 microns). The other group having 5.0 wt.% clonidine load and 3.8 wt. % clonidine load had a polymer core of DL5E and a polymer coating of DL 7E (sheath), which delayed drug release.The drug depot with the higher drug load released the fastest. Ingeneral, the higher the drug loads, the faster the drug release and morerelease of the drug from the depot, also the thicker the coating theslower the drug release.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain 3/4/5 pellet dose formulations of FIG. 15. Allformulations had either a 100 DL 5E coating on the core or a DL 7Ecoating on the core. All formulations had a lower initial burst effectas compared to uncoated pellets on day one, which was from about 3 mcg-5mcg and daily release ranged from 0.1 mcg to 5 mcg/day over about 55-92days. However, there was one formulation that had a high drug load of7.38 wt. % clonidine that had the fastest release over about 25 days anda peak release of about 13 mcg. This formulation may be useful where afast release is needed. All other formulations had consistent releaseafter the initial burst period with some having a release over 90 dayswith a release of from about 0.1 mcg/day to about 3 mcg/day.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.The formulation containing 10 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 120 days.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.The formulation containing 20 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 140 days, which is suitable for many chronicconditions.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.The formulation containing 7.5 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 145 days.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 3. Theformulation containing 5 wt. % clonidine drug load and the polymer 100DL 7E had about 100 cumulative release % of drug released from the depotas long as 175 days.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.The formulation containing 5 wt. % clonidine drug load, the polymer 8515DLG 7E and mPEG as a plasticizer had about 80 cumulative release % ofdrug released from the depot as long as 150 days.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.The formulation containing 5 wt. % clonidine drug load and the polymer8515 DLG 7E had about 75 cumulative release % of drug released from thedepot as long as 135 days.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 3.All formulations had about 50 to 75 cumulative release % of drugreleased from the depot as long as 160 days.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 3.All formulations had about 90 cumulative release % of drug released fromthe depot for 7 days. The formulations were of a smaller size (0.75mm×0.75 mm), which increases the surface area for release as compared todepots with larger diameters.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 3.All formulations had over 100 cumulative release % of drug released fromthe depot for over 30 days.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 3.Span 85 is a plasticizer for one formulation. All formulations had about30 to 50 cumulative release % of drug released from the depot for over50 days.

FIG. 27 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 3. Theformulation containing 5 wt. % clonidine drug load and the polymer 8515PLGA had about 100 cumulative release % of drug released from the depotas long as over 75 days.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 3. Theformulation containing 5 wt. % clonidine drug load and the polymer 8515PLGA and Span 65 as a plasticizer had about 65 cumulative release % ofdrug released from the depot as long as 70 days.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 3.All formulations had about 90 to 110 cumulative release % of drugreleased from the depot for over 100 days, except one, which had about90 cumulative release % of drug released from the depot for about 20days.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 3.All formulations had about 55 to 85 cumulative release % of drugreleased from the depot for over 28 days.

FIG. 31 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 3. Theformulation containing 10 wt. % clonidine drug load and the polymerDL-PLA had about 45 cumulative release % of drug released from the depotfor about 18 days.

FIG. 32 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 4.All formulations had POE and 10% or 20% clonidine drug load. Allformulations had about 80 to 90 cumulative release % of drug releasedfrom the depot for over 120 days, except one formulation, which releaseddrug within about 35 days.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 4. Theformulation containing 10 wt. % clonidine drug load and the polymer POEhad about 100% cumulative release % of drug released from the depot forabout 100 days.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 4. Theformulation had about 35% cumulative release % of clonidine releasedfrom the depot for about 23 days.

Example 4 Evaluation of Feeding Habits of Rats Receiving ClonidineImplants

Twenty-four Fisher 344 rats were utilized in this study. The twenty-fourrats were divided into 3 groups. Group 1 rats (8 in total) each receivedone strip implant comprising a high dosage of clonidine in a PLGApolymer. Group 2 rats (8 in total) each received one strip implantcomprising a low dosage of clonidine in a PLGA polymer. Group 3 rats (8in total) were the control in this study and did not receive anyimplant. Table 7 below shows the average number of rat food pelletsconsumed by rats in each of the 3 groups for 8 days after Group 1 and 2rats received strip implants.

TABLE 7 Average Number of Rat Food Pellets Consumed Days Group 1 Group 2Group 3 0 400 400 400 1 100 140 200 2 200 275 310 3 310 305 350 4 250260 300 5 280 320 320 6 285 350 420 7 285 375 375 8 400 400 400 Day 0 isbefore implantation

Each of the rats was examined following paw incision surgery and noovert behavioral differences were noticed between the rats implantedwith control, low dose clonidine PLGA implants and high dose clonidinePLGA implants. Further, none of the rats exhibited signs of sedation.All of the rats groomed normally and locomotion appeared to be normalfor all of the rats as well.

Post-hoc analysis of the differences between the 3 groups using Tukey'sHSD test found that the number of rat food pellets earned wassignificantly less for both low and high dose clonidine PLGA implantedgroups compared to the control group (Group 3). The number of foodpellets earned was significantly less for the high dose clonidine PLGAimplant group (Group 1) than the low dose clonidine PLGA implant group(Group 2).

Example 5 Evaluation of Weight Gain of Rats Receiving Fluocinolone

Forty Wistar rats were utilized in this study. The forty rats weredivided into 4 groups. Group 1 rats (10 in total) each receivedfluocinolone acetonide via systemic subcutaneous injection at a dosageof 0.5 ug/kg daily. Group 2 rats (10 in total) each receivedfluocinolone acetonide via systemic subcutaneous injection at a dosageof 5 ug/kg daily. Group 3 rats (10 in total) each received fluocinoloneacetonide via systemic subcutaneous injection at a dosage of 25 ug/kgdaily. Group 4 rats (10 in total) were the control in this study andreceived saline injections. FIG. 39 shows the average body weight forrats in each group during this study. As can be appreciated from FIG.39, rats receiving fluocinolone acetonide via systemic subcutaneousinjection at a dosage of 25 ug/kg daily for 22 days did not exhibit asmuch body weight increase as control rats.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. An implantable drug depot for weight control in a patient in need ofsuch treatment, the drug depot comprising at least one biodegradeablepolymer and at least one biologically active agent in an amount fromabout 0.1 wt. % to about 30 wt. % of the drug depot, wherein the drugdepot is capable of releasing said biologically active agent over aperiod of 5 to 135 days and said biologically active agent comprisesclonidine and/or fluocinolone.
 2. An implantable drug depot according toclaim 1, wherein said biologically active agent comprises from about 5wt. % to about 15 wt. % of the drug depot.
 3. An implantable drug depotaccording to claim 1, wherein said biologically active agent is releasedin an amount between 0.005 and 1.0 mg per day for a period of 5 to 135days.
 4. An implantable drug depot according to claim 1, wherein saidpolymer is capable of degrading in 200 days or less after said drugdepot is administered for weight control.
 5. An implantable drug depotaccording to claim 1, wherein the at least one biodegradable polymercomprises one or more of poly(lactide-co-glycolide) (PLGA), polylactide(PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof. 6.An implantable drug depot according to claim 1, wherein said clonidineis in the form of clonidine hydrochloride or a mixture of clonidine baseand a hydrochloride salt, and said fluocinolone comprises fluocinoloneacetonide.
 7. An implantable drug depot according to claim 1, whereinthe drug depot releases: (i) a bolus dose of the biologically activeagent; and (ii) an effective amount of the biologically active agentover a period of at least fifty days.
 8. A method for weight controlcomprising implanting a drug depot in an organism for weight control,wherein said drug depot comprises a biologically active agent in anamount from about 0.1 wt. % to about 30 wt. % of the drug depot and atleast one biodegradable polymer, and said biologically active agentcomprises clonidine and/or fluocinolone.
 9. A method according to claim8, wherein said biologically active agent comprises from about 5 wt. %to about 15 wt. % of the drug depot.
 10. A method according to claim 8,wherein said biodegradable polymer comprises at least 70 wt. % of thedrug depot.
 11. A method according to claim 8, wherein said biologicallyactive agent is capable of being released in an amount between 0.005 and1.0 mg per day for a period of 5 to 135 days.
 12. A method according toclaim 8, wherein the drug depot is capable of releasing about 5% toabout 100% of said biologically active agent relative to a total amountof said biologically active agent loaded in the drug depot over a periodof 3 to 200 days after the drug depot is implanted in said organism. 13.A method according to claim 8, wherein said clonidine is in the form ofclonidine hydrochloride or a mixture of clonidine and a hydrochloridesalt, and said fluocinolone comprises fluocinolone acetonide.
 14. Animplantable drug depot useful for weight control in a patient in need ofsuch treatment, the drug depot comprising at least one biodegradeablepolymer and a therapeutically effective amount of a clonidine and/orfluocinolone, the drug depot being administered at a site to controlweight, wherein the drug depot is capable of releasing the biologicallyactive agent at an amount between 0.005 and 1.0 mg per day for a periodof 5 to 135 days at the site.
 15. An implantable drug depot according toclaim 14, wherein said polymer is capable of degrading in 200 days orless after the drug depot is administered at the site.
 16. Animplantable drug depot according to claim 14, wherein said biologicallyactive agent is released in an amount between 0.01 and 0.1 mg per dayfor a period of 5 to 135 days at the site.
 17. An implantable drug depotaccording to claim 14, wherein said biologically active agent is presentin an amount of about 0.1 to about 30 wt. % of the drug depot and saidpolymer is present in an amount of about 70 to about 99.9 wt. % of thedrug depot.
 18. A method of making an implantable drug depot of claim 1,the method comprising combining a biocompatible polymer and atherapeutically effective amount of a biologically active agent or apharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.